The invention relates to an improved process for the preparation of 6-methylheptan-2-one and corresponding homologous methyl ketones, in particular phytone and tetrahydrogeranyl acetone, by aldolization of aldehydes with acetone in the presence of a polyhydric alcohol or aqueous solutions and suspensions, respectively, of an aldolization catalyst and a heterogeneous hydrogenation catalyst and a non-polar additive or auxiliary solvent.
The invention relates in particular to an industrial process for the production of methyl ketones by condensation of the corresponding aldehydes with acetone under hydrogenating conditions, wherein the methyl isobutyl ketone which is formed by acetone dimerization as a by-product is used as a selectivity-increasing additive and is partially circulated.
Methyl ketones, in particular 6-methylheptan-2-one, tetrahydrogeranyl acetone and phytone, are important intermediates and starting materials for the manufacture of fragrances, pharmaceutical products and animal feed additives (J. Org. Chem., 32 (1967), 177; J. Org. Chem., 28 (1963), 45; Bull. Soc. Chim. Fr. (1955), 1586), in particular of isophytol, which in turn constitutes a central building-block of vitamin E synthesis.
The preparation of methyl ketones, in particular methylheptanone, is described in the relevant literature, with various synthesis strategies being adopted. For instance, isoamyl halides and acetoacetic esters can be coupled with one another in a nucleophilic substitution reaction in the presence of stoichiometric quantities of a base(route A), with the xcex2-ketoester which arises as an intermediate being decarboxylated, with dissociation of the corresponding alcohol and carbon dioxide. Poor atom efficiency, the high level of waste CO2, alcohol production, and the salt burden which arises (Wagner et al., xe2x80x9cSynthetic Organic Chemistryxe2x80x9d, 327, John Wiley and Sons, Inc.) make the process uneconomic. 
Another synthesis strategy proceeds initially from the preparation of various unsaturated methylheptanone derivatives such as, for instance, 6-methyl-5-hepten-2-one or 6-methyl-3,5-heptadien-2-one (route B), which in a separate reaction step are hydrogenated to methylheptanone in the presence of heterogeneous catalysts (Izv. Akad. Nauk SSSR, Ser. Khim. 5 (1972), 1052). Disadvantages of this method are the cost of preparing the methylheptanone and the need for the method to be carried out as a multi-stage process.
A further possibility is oxidation of 6-methyl-5-hepten-2-ol (route C), as described in Recl. Trav. Chim. Pays Bas, 28, 116 (1909), or treatment of the alkenol with phosphoric acid and phosphorus(V) oxide (route D) in accordance with Bull. Soc. Chim. Fr., 1799, (1963). Both of these methods are unsuitable for the industrial preparation of methylheptanone because stoichiometric quantities of the corresponding reagents are consumed and synthesis of the educt is multi-stage and complex.
Numerous synthesis strategies have focused on the accessibility of 6-methyl-5-hepten-2-one from which, as outlined above (route B), the corresponding methylheptanone can be prepared efficiently by catalytic hydrogenation. Manufacturers of fragrances, aromas and vitamins have been fairly quick to recognize that 6-methyl-5-hepten-2-one constitutes a central intermediate from which it is possible to produce diverse vitamins, inter alia vitamin E and vitamin A, carotinoids and fragrances. The most important processes are discussed here by way of example.
Industrial use is made of a multi-stage process proceeding from acetone (route E) which in the first stage is converted in ammonia to methylbutinol in the presence of basic catalysts. Following Lindlar hydrogenation to methylbutenol a reaction with diketene then takes place and the intermediate which forms xe2x80x9cin situxe2x80x9d is converted to methylheptenone in a Caroll rearrangement (J. Org. Chem., 23, 153, (1958). It is obvious that the large number of stages in the process and the use of diketene and acetylene, and the associated high level of safety technology required, severely restrict the industrial applicability of the process.
A further process for the preparation of methylheptenone includes the pressure reaction of isobutene with formaldehyde and acetone (route F). The process conditions, which necessitate the application of high temperatures and pressures in order to obtain good conversions and selectivities, are, however, associated with high capital costs and restrict the applicability of the process (DE 12 59 876; DE 12 68 135; U.S. Pat. No. 3,574,773).
A different route to methylheptenone, which achieves its aim under moderate conditions, is a two-stage process which has in the meantime been scaled up to the industrial level. In the first step isoprene is reacted with HCl gas in the presence of a Cu-I halide, with an isomer mixture of the corresponding allyl chlorides arising. In a two-phase reaction with aqueous sodium hydroxide solution the terminal prenyl chloride is coupled with acetone in the presence of a phase transfer catalyst (route G). This process suffers from the disadvantages that a stoichiometric quantity of salt arises, and only moderate yields, of the order of 70%, are achieved (U.S. Pat. Nos. 3,983,175 and 3,984,475). 
In view of the problems indicated, selection of any of the synthesis strategies which have been indicated would appear to be uneconomic for the preparation of methylheptanone. In particular the route to 6-methylheptan-2-one by way of 6-methyl-5-hepten-2-one according to the prior art is associated only with a large number of stages and considerable capital cost.
A route to a double bond isomer of 6-methyl-5-hepten-2-one, namely 6-methyl-3-hepten-2-one, by cross-aldol condensation of isovaleraldehyde and acetone, in the presence of an aqueous alkali compound as a catalyst (Nippon Kagaku Kaishi, 59, 224 [1938]) constitutes an alternative process. The moderate reaction temperature which is adjusted in order to obtain high selectivities is also responsible for the reaction stopping at the xcex2-hydroxyketone stage (Bull. Soc. Chim. Fr., 112, [1957]).
In GB 1,246,698 acetone and isovaleraldehyde are reacted together at temperatures of  greater than 200xc2x0 C. and pressures of  greater than 30 bar, with only modest conversions of approx. 25% being obtained and acetone being used in a molar excess of 4 equivalents. In addition to the use of aqueous sodium hydroxide as a reaction catalyst, heterogeneous oxides are also described as aldolization catalysts.
DE-OS 26 15 308 (q.v. also U.S. Pat. No. 4,146,581) describes the use of catalytic quantities of rare earth oxides and simultaneously a heterogeneous hydrogenation catalyst (one or more metals from Group VIII of the Periodic Table) for the cross-aldolization of symmetrical ketones with low aldehydes (q.v. the reaction of acetone with isovaleraldehyde, Example 12), with the reaction being carried out at higher temperatures under hydrogenating conditions (in the presence of hydrogen, preferably at between 20 and 30 bar). According to a variant on this process, the aldolization catalyst utilized is not an oxide but a corresponding lipophilic salt (for example stearate). A disadvantage of this essentially sound process is the fact that in order to obtain high selectivities the ketone is used in a clear excess (3 to 5 equivalents in relation to the aldehyde utilized) and aldehyde conversion is incomplete. In this method a not inconsiderable component of the unreacted methylheptenone is also obtained in addition to the desired methylheptanone. No detail is provided as to the service lives of the heterogeneous systems which are used.
DE-OS 26 25 541 (corresponds to U.S. Pat. No. 4,212,825) also focuses on a method for the direct preparation of higher saturated ketones, in particular 6-methylheptanone, by cross-aldolization of acetone with 3-methylbutanal by the use of a heterogeneous supported contact catalyst which contains zinc oxide as the aldolizing component and nickel, cobalt or copper as the hydrogenating component. Disadvantages of this method are incomplete conversion, an unsatisfactory hydrogenation yield and the by-products which arise as a result of consecutive reaction of methylheptanone with a further equivalent of isovaleraldehyde (the product mixture contains 2,10-dimethylundecan-6-one and unsaturated precursors). Catalyst preparation is moreover costly. No detail is provided as to the long-term activity of the catalyst.
The use of zinc oxide xe2x80x9cper sexe2x80x9d as an aldolization catalyst for the preparation of the corresponding xcex1, xcex2-unsaturated ketones is described in U.S. Pat. No. 4,005,147. The use of lipophilic zinc salts in the presence of a hydrogenation catalyst is described in U.S. Pat. No. 3,316,303, in which considerable quantities of the unwanted alcohol result in particular from the use of an unsuitable hydrogenation catalyst (sulfide of the elements Mo, Ni, W or of a cobalt carbonylation catalyst).
A further approach to the preparation of 6-methylheptanone is described in WO 96/31454 according to which, in a two-stage process, in a first stage the cross-aldolization of acetone with isovaleraldehyde is first carried out in the presence of aqueous sodium hydroxide solution and, after a mixture containing 4-hydroxy-6-methyl-heptan-2-one has been obtained, dehydration and hydrogenation take place in the presence of a catalytic quantity of Brxc3x6nstedt acid and a heterogeneous noble metal hydrogenation catalyst. It is obvious that a multi-stage process, in particular the need to switch the catalyst medium from basic to acid, does not constitute a satisfactory solution to the present problems. In order to achieve high yields, moreover, an acetone excess of between 3 and 5 equivalents in relation to isovaleraldehyde is adjusted.
Another process is described in U.S. Pat. No. 5,955,636, in which aldolization of isovaleraldehyde with acetone is carried out in the presence of an aqueous sodium hydroxide solution and a heterogeneous noble metal hydrogenation catalyst, with the hydrogenation catalyst being suspended in an initial charge of acetone, and simultaneously both the aqueous sodium hydroxide solution and also isovaleraldehyde being dispensed into this suspension at elevated temperatures.
A disadvantage of this process is the cost of the process engineering which must be deployed for the simultaneous dispensing of the two solutions. After the reaction the heterogeneous hydrogenation catalyst must be removed by filtration, and this is then followed by phase separation, with the upper phase containing the substance of value, 6-methylheptanone, and the lower phase the aqueous sodium hydroxide solution diluted by the water of reaction. The conversions achievable by this process are approx. 97 to 98%, the yields in relation to isovaleraldehyde are approx. 87%. It becomes apparent when reproducing the patent that a substantial proportion of the isovaleraldehyde is hydrogenated to undesirable 3-methylbutan-1-ol. No detail is provided as to recycling and/or reactivation of the aqueous catalyst phase which contains both the alkaline aldolization catalyst and also the heterogeneous hydrogenation catalyst.
In the processes cited as prior art complete conversion is not normally sought because the selectivity of the aldolization falls as the conversion increases, a phenomenon attributed to consecutive reactions between the methylheptanone which has been formed and further equivalents of isovaleraldehyde, or to reactions of one of the intermediates xcex2-hydroxyketone or methylheptenone.
A further considerable disadvantage of the processes described is the need to utilize a large acetone excess in order to obtain high isovaleraldehyde selectivities. However, acetone tends under the given conditions to dimerize to mesityl oxide, which under hydrogenating conditions converts to methyl isobutyl ketone. In the processes described as prior art this homoaldolization of acetone constitutes a considerable side-reaction which markedly reduces the acetone selectivity and is manifested in a high specific consumption of ketone.
In particular all the proposed processes neglect the issue of how to recycle the catalyst phase, in particular the hydrogenation catalyst which dictates the economics of the process.
No economic process has hitherto been known which describes the preparation of methyl ketones, in particular 6-methylheptan-2-one, in which satisfactory yields are obtained at complete conversions (conversions  greater than 99%). Furthermore, a satisfactory process for preventing the undesirable by-product formation which results from the hydrogenation of isovaleral to 3-methylbutanol, and thus for reducing the specific consumption of isovaleral, has hitherto proved elusive.
The object of this invention was to find a process for the generation of methyl ketones by cross-aldolization of acetone with the corresponding aldehydes under hydrogenating conditions, which
a.) enables the corresponding methyl ketones to be prepared at optimal yields and purities with complete conversion ( greater than 99%) of the aldehyde utilized, while avoiding a costly process regime, namely the simultaneous addition of both the aqueous alkali solution and the aldehyde,
b.) enables a simple recycling of the unreacted or unconsumed educts and auxiliary solvent, in particular acetone, the active hydrogenation catalyst, and thus allows consistently stable yields and process conditions to be achieved with repeated utilization of the reactivated catalyst, and
c.) prevents undesirable hydrogenation of the aldehyde utilized to the corresponding primary alcohol.
The process according to the invention is an industrial circulating process with partial recirculation of the auxiliary solvent and/or methylheptanone, in which the non-polar auxiliary solvents according to the invention exert a selectivity-enhancing effect. A further aspect of the present invention is the utilization of the said methyl ketones as an educt for the preparation of isophytol and vitamin E acetate as a result of passing successively through reaction sequences C2, C3 chain lengthening and partial hydrogenation steps.
The invention relates to a process for the preparation of methyl ketones corresponding to the general formula (1) 
wherein x represents a number between 1 and 3 (for x=1xe2x86x926-methylheptan-2-one; for x=2xe2x86x92tetrahydrogeranyl acetone; for x=3xe2x86x92phytone) by reacting hydrogen, acetone and an aldehyde corresponding to the general formula (2) 
wherein x represents a number between 0 and 2 and the broken lines in each case represent olefinic double bonds, characterized in that the reaction of the components is carried out in the presence of a catalyst suspension which contains a suspended heterogeneous hydrogenation catalyst and a dissolved aldolization catalyst containing alkali metal or alkaline earth metal, and that the reaction of the components is carried out in two-phase manner, wherein the lower, water or alcohol, phase constitutes the suspension medium of the heterogenous hydrogenation catalyst and the solvent of the aldolization catalyst, and the upper phase constitutes a solution of acetone (reagent) in a non-polar auxiliary solvent, in particular methyl isobutyl ketone.
It is important that the process according to the invention is utilized as a two-phase process for the preparation of methyl ketones, in particular 6-methylheptan-2-one, by co-aldolization of aldehydes, in particular isovaleraldehyde, with acetone under hydrogenating conditions.
It has been found after intensive investigation that the problems indicated above are resolved in surprising manner, in that
1) the catalyst phase is introduced into an autoclave as an initial charge together with acetone as a two-phase mixture under hydrogen and, with efficient stirring ensured, the corresponding aldehyde is pumped in at temperatures of between 40xc2x0 C. and 200xc2x0 C., and after termination of the reaction, following separation of the heterogeneous hydrogenation catalyst, the upper phase which contains the substance of value (the corresponding methyl ketone along with unreacted acetone) is removed from the water phase or alcohol phase and acetone is recovered by distillation and the corresponding methyl ketone is isolated; and
2) after termination of the reaction, the methyl isobutyl ketone formed during the reaction is obtained, along with acetone, by distillation of the organic product phase, and is returned wholly or partially into the reaction as a recycle stream, wherein methyl isobutyl ketone, being a comparatively non-polar solvent, ensures that the reaction batch is two-phase at the beginning of the reaction, and optionally
3) a further non-polar auxiliary solvent is circulated when the process is carried out as a continuous process.
In particular an improved process is described for the preparation of asymmetrically substituted ketones carrying an xcex1-methyl group, which are designated herein-below as methyl ketones, by reacting the corresponding aldehydes with acetone under hydrogenating, dehydrating and aldolizing conditions, wherein the educts used and the products arising have low solubility in the catalyst phase which contains both the hydrogenation catalyst and also the alkaline dehydration and aldolization catalyst.
The addition according to the invention of a non-polar auxiliary solvent, in particular the recycling of this auxiliary solvent when the process is operated as a continuous process, enables previously undescribed yields of up to 98% in relation to aldehyde utilized, to be achieved.
A further aspect of the invention is the two-phase reaction regime with use of a polyhydric polar alcohol as the suspending medium of the heterogeneous hydrogenation catalyst or aqueous solutions of the said polyhydric alcohols or in the simplest instance, water itself, and the separation of the product phase from the active catalyst phase following filtration of the hydrogenation catalyst, phase separation and working-up of the two phases, with recirculation of unreacted educts and auxiliary substances.
Admittedly, methyl isobutyl ketone is formed as a by-product of the undesirable acetone homoaldolization in all the processes described in the prior art, yet in these processes the methyl isobutyl ketone concentration increases only as the duration of the reaction increases, that is to say, at the beginning of the reaction absolutely no methyl isobutyl ketone is present.
According to the present process, by recycling methyl isobutyl ketone and/or methylheptanone from the working-up of the products, a concentration of methyl isobutyl ketone and/or methylheptanone sufficient to increase markedly the yield of the reaction is now adjusted even at the beginning of the reaction.
After the two-phase reaction mixture has been introduced as the initial charge, the optionally unsaturated aldehyde is dispensed-in, such that the xe2x80x9cin situxe2x80x9d concentration thereof in the reaction mixture is at all times below 20 mol. % in relation to acetone. After the reaction has run, the two-phase mixture in which the hydrogenation catalyst is suspended is filtered, with the heterogeneous hydrogenation catalyst being separated and an unequivocally two-phase mixture resulting. The phase containing the aldolization catalyst is separated. The working-up of the two phases by distillation recovers unreacted acetone virtually quantitatively along with smaller aldehyde residues and enables the methyl ketones which are desired as the product to be isolated at purities of  greater than 99%.
Taking as an example the acetonization of 3-methylbutyraldehyde (isovaleraldehyde) with preparation of methylheptanone, the reaction is outlined in the diagram below. The compounds shown in brackets are passed through as intermediates: 
Catalyst phase here means a phase which contains the aldolization catalyst and the hydrogenation catalyst. The catalyst phase is itself likewise two-phase because the aldolization catalyst is present dissolved and the heterogeneous hydrogenation catalyst is suspended.
The process according to the invention substantially improves the process regime over that of the method described in the prior art, in that the dispensing of only one component is necessary in order for high selectivities to be achieved, and virtually quantitative yields of the desired methyl ketones in relation to aldehyde utilized can be achieved. The circulating of a non-polar auxiliary solvent, in particular the recycling of methyl isobutyl ketone or of methylheptanone itself, the product of the reaction, represents only a minor expense because methyl isobutyl ketone necessarily arises in the process as a by-product of acetone dimerization and must be separated from the product by distillation.
The high yields achieved result in a dramatic reduction in high-boiling by-products which promote the deactivation of the hydrogenation catalyst and severely limit its recyclability. Avoiding the formation of 3-methylbutanol by isovaleral hydrogenation, which arises when working in accordance with U.S. Pat. No. 5,955,636, facilitates product isolation by obviating the need to carry out corresponding separating operations.
In the highly selective process according to the invention (sic) the recyclability of the heterogeneous hydrogenation catalyst is unrestricted. Under optimal conditions the catalyst may be utilized up to 30 times or more with no appreciable loss of hydrogenating activity.
The hydrogenation catalyst is separated by standard industrial measures, in the simplest instance by filtration. The catalyst phase and product phase are in the simplest instance separated by simple decanting. The catalyst phase thus obtained contains more or less all the water of reaction which arises as a result of the condensation, thus, by avoiding formation of azeotropes between water and the carbonyl compounds or other substances present, substantially facilitating the working-up by distillation of the organic product phase. The catalyst phase contains the unconsumed alkaline aldolization catalyst and the alkali salt or alkaline earth salt of the acid corresponding to the aldehyde, the product of a Cannizzaro reaction which is observed as a side-reaction. The sodium salt of isovaleric acid arises as a by-product of the reaction of isovaleral with aqueous sodium hydroxide solution.
Before re-use of the water phase or alcohol phase the quantity of alkali consumed by side-reactions is merely replenished.
The process according to the invention consequently makes possible an industrial one-pot concept for the preparation of methyl ketones, in which the catalyst phase may be, optionally completely, returned after the reaction has been carried out and the phases have been separated. In a different variant according to the invention the alkaline catalyst solution is discarded after removal of the organic constituents and optionally neutralization.
The reaction regime provides simple dispensing of the aldehyde into the two-phase mixture of catalyst phase, acetone and non-polar auxiliary solvent, in particular methyl isobutyl ketone, thus giving rise to only minor control engineering costs. In this way a safe process regime is further ensured because heat which is generated is simply restrained by interrupting or slowing down the dispensing of aldehyde.
The first aspect of the invention relates to a process for the preparation of methyl ketones, in particular 6-methylheptan-2-one, from the corresponding carbonyl compound and acetone, characterized in that both the alkaline condensation catalyst and also the heterogeneous hydrogenation catalyst are dissolved and suspended, respectively, in a polyhydric lipophobic alcohol and/or water, and the reaction is carried out in two-phase manner in the presence of a non-polar auxiliary solvent, in particular methyl isobutyl ketone.
This first aspect also includes the method by which the lipophobic alcohol phase or water phase containing the catalysts, acetone and the auxiliary solvent is introduced as an initial charge into an autoclave under a moderate hydrogen pressure and the aldehyde component is dispensed into the two-phase mixture of acetone/auxiliary solvent and catalyst phase. It should be ensured here that the aldehyde concentration in the reaction solution should be selected to be as low as possible and does not exceed a concentration of 20 mol. % in relation to acetone utilized. This method can be realized in simple manner if the aldehyde addition takes place over a dispensing period of from 0.5 to 5 hours, at a corresponding reaction temperature. The presence of the auxiliary solvent even at the beginning of the reaction produces two-phase conditions, such that the product arising is removed from the catalyst phase at the moment of formation, in the sense of a reactive extraction.
In order to aid understanding, the reaction will be explained by way of example at this juncture, taking as the example the reaction of acetone with isovaleraldehyde for the preparation of 6-methylheptan-2-one. The reaction proceeds xe2x80x9cin situxe2x80x9d by way of the aldolization ""stage, with the corresponding xcex2-hydroxyketone arising, which is not isolated. Under the reaction conditions dehydration to 6-methylhept-3-en-2-one takes place, and this is hydrogenated selectively to the corresponding methyl ketone by the hydrogenation catalyst which is distributed homogeneously in the lipophobic alcohol phase.